Strategies to reduce late-stage drug attrition due to mitochondrial toxicity

Abstract

Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities and negative side-effect profiles. Early identification of mitochondrial liabilities for new chemical entities is therefore crucial for avoiding late-stage attrition during drug development. Limitations of traditional methods for assessing mitochondrial dysfunction have discouraged routine evaluation of mitochondrial liabilities. To circumvent this bottleneck, a high-throughput screen has been developed that measures oxygen consumption; one of the most informative parameters for the assessment of mitochondrial status. This technique has revealed that some, but not all, members of many major drug classes have mitochondrial liabilities. This dichotomy encourages optimism that efficacy can be disassociated from mitochondrial toxicity, resulting in safer drugs in the future.

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…Of the ten most common drugs associated with drug-induced liver fatality, mitochondrial dysfunction/disruption is a major component in at least five of them. Furthermore, mitochondrial dysfunction plays a key role in non-hepatic drug toxicities such as cardiomyopathy and rhabdomyolysis [10][11][12][13].…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…34 With statin cessation, liver chemistry elevations resolved within 2-8 weeks. Reactive metabolite 32 20-160 mg 26 Atorvastatin, simvastatin, lovastatin (n ¼ 10) 34 30% 34 Decreases mitochondrial membrane potential; inhibits fatty acid beta-oxidation 36 ; uncouples electron transport from phosphorylation 37 Atorvastatin electrophilic acyl glucuronide metabolite 35 20-80 mg 26 Isoniazid, rifampin, pyrazinamide (n ¼ 220) 6 Statin injury is predominantly hepatocellular. 33 The formation of electrophilic metabolites covalently binding to proteins is frequently implicated in immunebased hepatotoxicity; an electrophilic acyl glucuronide metabolite has been reported for atorvastatin.…”

“…36 In isolated rat hepatic mitochondria, simvastatin uncouples electron transport from phosphorylation. 37 Statin-induced mitochondrial impairment and/or reactive metabolite formation contributes to rechallenge injury.…”

“…37 Mitochondrial dysfunction arises from multiple mechanisms: oxidative stress; opening of the mitochondrial transition pore, which depletes the mitochondrial membrane potential; inhibiting or uncoupling electron transport, which diminishes ATP production; inhibiting fatty acid oxidation; and inhibiting synthesis of mitochondrial DNA or proteins, which prevents the replacement of damaged mitochondria with newly formed functional mitochondria. 37 Approximately onethird of over 500 pharmaceuticals inhibit mitochondrial respiration or impair electron transport. 46 Mitochondrial dysfunction can be caused by a diverse array of drugs, including antibiotics, antiretrovirals, antidepressants, antianginals, nonsteroidal anti-inflammatory agents, anticonvulsants, anesthetics, antiarrhythmics, and oncology agents.…”

“…46 Mitochondrial dysfunction can be caused by a diverse array of drugs, including antibiotics, antiretrovirals, antidepressants, antianginals, nonsteroidal anti-inflammatory agents, anticonvulsants, anesthetics, antiarrhythmics, and oncology agents. 37,47 In drugs initiating mitochondrial dysfunction, liver injury develops gradually over weeks, because cumulative mitochondrial impairment reaches a critical threshold with clinically evident liver injury (apoptosis or necrosis). 8 Regeneration of individual mitochondria and full cellular repopulation of mitochondria takes several weeks.…”